Method of producing oxazolidinones, the use thereof and novel oxazolidinones

ABSTRACT

The invention concerns a method of producing oxazolidinones of formula (I), wherein R 1  -R 5  have the meanings given in the description, by reacting cyclical anhydrides of formula (II) with carbonyl compounds of general formula (III) at temperatures between ambient temperature and approximately 150° C. The invention also concerns the production of the cyclical anhydrides of formula (II) by reacting N-protected aminodicarboxylic acids of formula (IV) with a dehydrating agent in situ. The invention further concerns the use of oxazolidinones of formula (I) for the α-selective production of esters of formula (V) and amides of general formula (VII).

This application is the national phase of international applicationPCT/EP96/00390, filed Jan. 31, 1996 which was designated the U.S.

The invention is relative to methods of producing oxazolidinones ofgeneral formula I ##STR1## in which R¹ signifies hydrogen; (C₁-C₁₂)-alkyl; (C₂ -C₁₀)-alkenyl; (C₂ -C₁₀)-alkenyl; (C₁ -C₆)-alkyl whichis substituted singly or multiply by equal or different groups from thegroup of halogen, (C₁ -C₄)-alkoxy, (C₁ -C₄)-alkylthio, --CN, (C₂-C₅)-alkoxycarbonyl and (C₂ -C₆)-alkenyl; (C₃ -C₈)-cycloalkyl which isunsubstituted or substituted by one or more groups from the group (C₁-C₄)-alkyl, (C₁ -C₄)-alkoxy, (C₁ -C₄)-alkylthio and halogen; (C₅-C₈)-cycloalkenyl; aryl or aryl-(C₁ -C₄)-alkyl which are unsubstitutedor substituted in the aryl group; --OR⁶ ; NR⁷ R⁸ ; or stands inconjunction with the adjacent carbonyl group for a protective group,especially boac, Z, TFA, aloc, teoc, formyl, tosyl, mesyl, fmoc, moc,suitable for protecting the amino group of an amino acid;

R² and R³ signify, independently of one another and equally ordifferently hydrogen, (C₁ -C₈)-alkyl or (C₃ -C₈)-alkenyl, (C₃-C₈)-alkenyl or (C₃ -C₈)-cycloalkyl,

which above C-containing groups can be unsubstituted or substitutedsingly or multiply, preferably up to three times, by equal or differentgroups from the group containing halogen, hydroxy, (C₁ -C₈)-alkoxy, (C₁-C₈)-alkylmercapto, (C₂ -C₈)-alkenylmercapto, (C₂ -C₈)-alkinylmercapo,(C₂ -C₈)-alkenyloxy, (C₂ -C₈)-alkinyloxy, (C₃ -C₇)-cycloalkyl, (C₃-C₇)-cycloalkoxy, cyano, mono- and di-(C₁ -C₄ -alkyl)-amino, aryl,aryl-(C₁ -C₆)-alkoxy, which last two groups cited in the aryl ring canbe unsubstituted or substituted singly or multiply, preferably up tothree times, by equal or different groups from the group of halogen, (C₁-C₄)-alkyl, (C₁ -C₄)-alkoxy, (C₁ -C₄)-halogen alkyl, (C₁ -C₄)-halogenalkoxy; and

which groups R² and R³ can be connected together to a 3-10-member ringwhich can also be N, O, S-heterosubstituted itself in addition to thecited substituents;

R⁴ can be hydrogen, (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl, (C₂ -C₆)-alkinyl,aryl, alkaryl, aryl alkyl or cycloalkyl and the linear as well as thebranched alkyl groups can contain halogen- and/or heteroatomsubstitution (N, O, S) either singly or multiply, just as the aliphaticor aromatic cycles;

R⁵ signifies a (C₁ -C₂)-alkane diyl chain which can be substituted withup to four (C₁ -C₄)-alkyl groups, (C₃ -C₄)-alkenyl groups, (C₃-C₄)-alkinyl groups, (C₃ -C₈)-cycloalkyl groups and/or aryl groups,which alkane diyl chain itself as well as its substituents can be N, O,S-heterosubstituted

and two of the substituents of the alkane diyl chain can be connected toone another or one of the substituents of the alkane diyl chain with R⁴even to a ring;

R⁶ signifies hydrogen, (C₁ -C,₈)-alkyl, (C₃ -C₁₂)-cycloalkyl, (C₂-C₈)-alkenyl or (C₂ -C₈)-alkinyl, which above C-containing groups areunsubstituted or substituted singly or multiply, preferably up to threetimes, by equal or different groups from the group containing halogen,hydroxy, (C₁ -C₈)-alkoxy, (C₁ -C₈)-alkylmercapto, (C₂-C₈)-alkenylmercapto, (C₂ -C₈)-alkinylmercapto, (C₂ -C₈)-alkenyloxy, (C₂-C₈)-alkinyloxy, (C₃ -C₇)-cycloalkyl, (C₃ -C₇)-cycloalkoxy, cyano, mono-and di-(C₁ -C₄ -alkyl)-amino, carboxy, (C₁ -C₈)-alkoxycarbonyl,

(C₂ -C₈)-alkenyloxycarbonyl,

(C₁ -C₈)-alkylmercaptocarbonyl,

(C₂ -C₈)-alkinyloxycarbonyl,

(C₁ -C₈)-alkylcarbonyl, (C₂ -C₈) alkenylcarbonyl,

(C₂ -C₈)-alkinylcarbonyl, 1-(hydroxy imino),

(C₁ -C₆)-alkyl, 1-[(C₁ -C₄)-alkylimino]-(C₁ -C₄) -alkyl, 1-[(C₁-C₄)-alkoxyimino]-(C₁ -C₆)-alkyl,

(C₁ -C₈)-alkylcarbonyl amino, (C₂ -C₈)-alkenylcarbonyl amino,

(C₂ -C₈)-alkinylcarbonyl amino, amino carbonyl,

(C₁ -C₈)-alkylamino carbonyl,

di-(C₁ -C₆)-alkylamino carbonyl,

(C₂ -C₆)-alkenylamino carbonyl,

(C₂ -C₆)-alkinylamino carbonyl,

(C₁ -C₈)-alkoxycarbonyl amino,

(C₁ -C₈)-alkylamino carbonyl amino,

(C₁ -C₆)-alkylcarbonyloxy, which is unsubstituted or substituted byhalogen, nitro, (C₁ -C₄)-alkoxy or optionally substituted phenyl, (C₂-C₆)-alkenylcarbonyloxy, (C₂ -C₆)-alkinylcarbonyloxy, (C₁ -C₈)-alkylsulfonyl, phenyl, phenyl-(C₁ -C₆)-alkoxy, phenyl-(C₁ -C₆)-alkoxycarbonyl, phenoxy, phenoxy-(C₁ -C₆)-alkoxy, phenoxy-(C₁ -C₆)-alkoxycarbonyl, phenylcarbonyloxy, phenylcarbonyl amino, phenyl-(C₁-C₆)-alkylcarbonyl amino, which last-named 9 groups in the phenyl ringare unsubstituted or substituted simply or multiply, preferably up tothree times, by equal or different groups from the group of halogen, (C₁-C₄) -alkyl, (C₁ -C₄)-alkoxy, (C₁ -C₄)-halogen alkyl, (C₁ -C₄)-halogenalkoxy and nitro, and [containing] groups of the formulas --SiR'₃,--O--SiR'₃, R'₃ Si--(C₁ -C₈)-alkoxy, --CO--O--NR'₂, --O--N═CR'₂,--N═CR'₂, --O--NR'₂, CH(OR')₂ and --O--(CH₂)_(m) --CH(OR)₂ in which theR's in the cited formulas signify independently of each other hydrogen,(C₁ -C₄)-alkyl, phenyl, which is unsubstituted or substituted singly ormultiply, preferably up to three times, by equal or different groupsfrom the group of halogen, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, (C₁-C₄)-halogen alkyl, (C₁ -C₄)-halogen alkoxy and nitro, or signify inpairs a (C₂ -C₆)-alkane diyl chain and m=0 to 6, and [containing] asubstituted alkoxy group of the formula R"O--CHR'"(OR")--(C₁ -C₆)-alkoxyin which the R" signify independently of each other (C₁ -C₄)-alkyl ortogether (C₁ -C₆)-alkane diyl and R"" signifies hydrogen or (C₁-C₄)-alkyl, and

R⁷ and R⁸ have a significance, independently of one another and equallyor differently, indicated for R⁶ and R⁷ and R⁸ can also be connectedamong themselves to a ring;

as well as is relative, e.g., to novel oxazolidinones obtainableaccording to the method of the invention and to the use ofoxazolidinones.

1,3-oxazolidin-5-ones are especially significant as activatedintermediates in the α-selective reaction of α-amino dicarboxylic acidswith nucleophiles. Esters or amides can be produced from α-aminodicarboxylic acids by reacting oxazolidinones with alcohols or amines inapproximately 100% α-regioselectivity under almost complete preservationof the optical activity of the initial product at the same time, thatis, with decidedly high enantioselectivity.

α-acid derivatives of aspartic acid and glutamic acid are used aspharmaceutical agents such as e.g. CCK antagonists (Drugs of the Future,1993, 18, 919-31) and as sweeteners such as e.g. alitame (EP 34,876),aspartame (DE 21 07 411) and L-Asp-D-α-amino alkanoyl-(S)-α-alkylbenzylamides (WO 94/00028).

A protection of the β- and γ-carboxyl function such, e.g., as ester isnecessary for the α-selective production of these substances. If thisdoes not take place, mixtures of α- and β- and/or γ-substitutionproducts result which must be purified in an expensive manner. This isthe case if the readily producible inner anhydrides of general formulaII are used for coupling (Houben-Weyl, volume 15/1, J. Chem. Soc. 1950,1954, J. Chem. Soc. 1952, 24, DE 21 07 411, WO 87/03869).

The invention had the problem of developing a method permitting anα-selective coupling of Asp and Glu using the relatively simplyproducible inner anhydrides. Furthermore, the invention had the problemof indicating novel N-acylated oxazolidinone derivatives which shouldpermit as intermediate products the α-selective coupling with amines oralcohols with the obtention of esters and amides from α-aminodicarboxylic acids.

These and other problems not cited in detail are solved with a method byreacting cyclic anhydrides of general formula II ##STR2## in which R¹,R⁴ and R⁵ have the significance indicated for formula I with carbonylcompounds of general formula III ##STR3## in which R² and R³ have thesignificance indicated for formula I, or with compounds which produce,as precursors of the compounds of formula III under the conditions ofthe reaction, compounds of formula III during the reaction attemperatures between room temperature and approximately 150° C.,preferably in the presence of catalytic amounts of acids.

In a preferred embodiment of the invention the cyclic anhydrides ofgeneral formula II can be obtained by reacting N-protected aminodicarboxylic acids of general formula IV ##STR4## in which R¹, R⁴ and R⁵have the significance indicated for formula I with a dehydrating agentat temperatures between -20° C. and approximately 150° C. According tothe invention it is not necessary thereby to isolate the inneranhydrides of general formula II, but rather they can be produced insitu.

Thus, in the above-named variant the oxazolidinone of general formula Ican be obtained directly from the α-amino dicarboxylic acids of generalformula IV without taking the path via the isolation of the anhydrideaccording to formula II. If, on the other hand, the anhydride of generalformula II accumulates in a synthetic process, the target product offormula I striven for can be produced starting from the latter inlikewise high yield and purity.

In an advantageous method variant all substances commonly known to anexpert in the art can be used as dehydrating agents which substances canbring about the formation of an inner anhydride from a dicarboxylicacid. The dehydrating agents which can be used in the reaction of theinvention include, among others, phosphorus pentoxide, thioyl chloride,orthoester, acetic hydride, etc. Acetic anhydride is especiallypreferred.

It has proven to be advantageous for the method of the invention tocarry out the reaction in an organic solvent. All organic solvents whichare inert under the reaction conditions to the reactants are suitable assolvent. Due to their good solvent power for anhydrides, organiccarboxylic acids or their derivatives are especially preferred.Carboxylic acids with 1 to 5 C atoms are particularly preferred. Aceticacid is an especially preferred solvent.

The reaction for producing the N-acyl oxazolidinones of general formulaI is preferably carried out at elevated temperatures between 50 and 150°C. A temperature range between 70 and 120° C. has proven to beespecially advantageous.

All protonic acids and Lewis acids can be used as catalytically activeacid within the framework of the invention. The following are possible,among others: Sulfuric acid, hydrochloric acid, trifluoroacetic acid,sulfonic acids, p-TosOH, etc. Sulfonic acids are preferable and p-TosOHis especially preferable.

The method of the invention can be carried out with special success inthe case of those compounds of formulas II or IV in which R⁴ stands forH and R⁵ for --CH₂ -- or --CH₂ --CH₂ --. In the case of R⁵ ═--CH₂--derivatives of aspartic acid are present and in the case of R⁵ ═--CH₂--CH₂ --derivatives of glutamic acid or of the particular cyclicanhydrides are present.

Furthermore, it is also particularly advantageous within the frameworkof the invention that compounds are reacted in which R¹ stands for H,that is, the α-amino group is formyl-protected.

In addition, it is preferred in a further special method variant of theinvention to react compounds of formula III in which R² and R³ arehydrogen. Although it is possible according to the invention and is alsopreferred in many instances to use any ketones or aldehydes as carbonylcompounds, the realization of the invention succeeds especially well ifformaldehyde is used. In addition, formaldehyde has the additionaladvantage that it can also be used as a readily manageable depot form.

Thus, any depot form releasing formaldehyde in the actual reaction canbe used as precursor of formaldehyde. Paraformaldehyde or trioxane,among others, are preferred. The splitting of these depot forms underthe conditions of the reaction takes place acidically with a protonicacid or Lewis acid preferably used as catalyst for the splitting.Sulfonic acids, p-TosOH, trifluoroacetic acid, thionyl chloride,sulfuric acid, etc., among others, are possible. P-TosOH is preferred.

Novel oxazolidinones of general formula I also constitute subject matterof the invention ##STR5## in which R¹ is hydrogen;

R² and R³ signify, independently of one another and equally ordifferently hydrogen, (C₁ -C₈)-alkyl or (C₃ -C₈)-alkenyl, (C₃-C₈)-alkinyl or (C₃ -C₈)-cycloalkyl,

which above C-containing groups can be unsubstituted or substitutedsingly or multiply, preferably up to three times, by equal or differentgroups from the group containing halogen, hydroxy, (C₁ -C₈)-alkoxy, (C₁-C₈)-alkylmercapto, (C₂ -C₈)-alkenylmercapto, (C₂ -C₈)-alkinylmercapo,(C₂ -C₈)-alkenyloxy, (C₂ -C₈)-alkinyloxy, (C₃ -C₇)-cycloalkyl, (C₃-C₇)-cycloalkoxy, cyano, mono- and di-(C₁ -C₄ -alkyl)-amino, aryl,aryl-(C₁ -C₆)-alkoxy, which last two groups cited in the phenyl ring canbe unsubstituted or substituted singly or multiply, preferably up tothree times, by equal or different groups from the group of halogen, (C₁-C₄)-alkyl, (C₁ -C₄)-alkoxy, (C₁ -C₄)-halogen alkyl, (C₁ -C₄)-halogenalkoxy; and

which groups R² and R³ can be connected together to a 3-10-member ringwhich can also be N, O, S-heterosubstituted itself in addition to thecited substituents;

R⁴ can be hydrogen, (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl, (C₂ -C₆)-alkinyl,aryl, alkaryl, aryl alkyl or cycloalkyl and the linear as well as thebranched alkyl groups can contain halogen- and/or heteroatomsubstitution (N, O, S) either singly or multiply, just as the aliphaticor aromatic cycles;

R⁵ signifies a (C₁ -C₂)-alkane diyl chain which can be substituted withup to four (C₁ -C₄)-alkyl groups, (C₃ -C₄)-alkenyl groups, (C₃-C₄)-alkinyl groups, (C₃ -C₈)-cycloalkyl groups and/or aryl groups,which alkane diyl chain itself as well as its substituents can be N, O,S-heterosubstituted

and two of the substituents of the alkane diyl chain can be connected toone another or one of the substituents of the alkane diyl chain with R⁴even to a ring;

with the exception of the oxazolidinone of formula I with R² ═H, R³═CCl₃, R⁵ ═CH₂ and R⁴ ═H.

Oxazolidinones in which R⁴ is hydrogen and R⁵ is --CH₂ -- or --CH₂ --CH₂-- are preferred.

Oxazolidinones in which R² and R³ are each hydrogen are also preferred.

Subject matter of the invention is also constituted by oxazolidinones ofgeneral formula I in which R¹ is aryl and the aromatic ring can carryhalogen or other substituents up to threefold and R² --R⁴ are hydrogenand R⁵ is --CH₂ -- or --CH₂ --CH₂ --.

The novel oxazolidinones are coupled in an especially advantageousmanner in the presence of an auxiliary base e.g. with protected aminoacids, yielding α-selectively N-acyl-protected coupling products.Although the coupling products can be produced e.g. even without the useof the oxazolidinones of general formula I produced in accordance withthe invention or of the novel oxazolidinones of general formula I inaccordance with the invention, the use of the oxazolidinones inaccordance with the invention is preferred since the α-selectivity e.g.in the coupling of compounds of general formula II with alcohols oramines is distinctly below 100% and in many instances only at about 80 %or less.

Therefore, the invention also has as subject matter the use ofoxazolidinones indicated herein for the α-selective production of estersof general formula V ##STR6## in which R¹ and R⁵ have the significanceindicated for formula I and

R⁹ signifies hydrogen, (C₁ -C₁₈)-alkyl, (C₃ -C₁₂)-cycloalkyl, (C₂-C₈)-alkenyl or (C₂ -C₈)-alkinyl, which above C-containing groups areunsubstituted or substituted singly or multiply, preferably up to threetimes, by equal or different groups from the group containing halogen,hydroxy, (C₁ -C₈)-alkoxy, (C₁ -C₈)-alkylmercapto, (C₂-C₈)-alkenylmercapto, (C₂ -C₈)-alkinylmercapto, (C₂ -C₈)-alkenyloxy, (C₂-C₈)-alkinyloxy, (C₃ -C₇)-cycloalkyl, (C₃ -C₇)-cycloalkoxy, cyano, mono-and di-(C₁ -C₄ -alkyl)-amino, carboxy, (C₁ -C₈)-alkoxycarbonyl, (C₂-C₈)-alkenyloxycarbonyl, (C₁ -C₈)-alkylmercaptocarbonyl, (C₂-C₈)-alkinyloxycarbonyl, (C₁ -C₈)-alkylcarbonyl, (C₂ -C₈)alkenylcarbonyl, (C₂ -C₈)-alkinylcarbonyl, 1-(hydroxy imino)-(C₁-C₆)-alkyl, 1-[(C₁ -C₄)-alkylimino]-(C₁ -C₄)-alkyl, 1-[(C₁-C₄)-alkoxyimino]-(C₁ -C₆)-alkyl, (C₁ -C₈)-alkylcarbonyl amino, (C₂-C₈)-alkenylcarbonyl amino, (C₂ -C₈)-alkinylcarbonyl amino, aminocarbonyl, (C₁ -C₈)-alkylamino carbonyl, di-(C₁ -C₆)-alkylamino carbonyl,(C₂ -C₆)-alkenylamino carbonyl, (C₂ -C₆)-alkinylamino carbonyl, (C₁-C₈)-alkoxycarbonyl amino, (C₁ -C₈)-alkylamino carbonyl amino, (C₁-C₆)-alkylcarbonyloxy, which is unsubstituted or substituted by halogen,nitro, (C₁ -C₄)-alkoxy or optionally substituted phenyl, (C₂-C₆)-alkenylcarbonyloxy, (C₂ -C₆)-alkinylcarbonyloxy, (C₁-C₈)-alkylsulfonyl, phenyl, phenyl-(C₁ -C₆)-alkoxy, phenyl-(C₁-C₆)-alkoxycarbonyl, phenoxy, phenoxy-(C₁ -C₆)-alkoxy, phenoxy-(C₁-C₆)-alkoxycarbonyl, phenylcarbonyloxy, phenylcarbonyl amino, phenyl-(C₁-C₆)-alkylcarbonyl amino, which last-named 9 groups in the phenyl ringare unsubstituted or substituted simply or multiply, preferably up tothree times, by equal or different groups from the group of halogen, (C₁-C₄)-alkyl, (C₁ -C₄)-alkoxy, (C₁ -C₄)-halogen alkyl, (C₁ -C₄)-halogenalkoxy and nitro, and [containing] groups of the formulas --SiR'₃,--O--SiR'₃, R'₃ Si--(C₁ -C₈)-alkoxy, --CO--O--NR'₂, --O--N═CR'₂,--N═CR'₂, --O--NR'₂, CH(OR')₂ and --O--(CH₂)_(m) --CH(OR)₂ in which theR's in the cited formulas signify independently of each other hydrogen,(C₁ -C₄)-alkyl, phenyl, which is unsubstituted or substituted singly ormultiply, preferably up to three times, by equal or different groupsfrom the group of halogen, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, (C₁-C₄)-halogen alkyl, (C₁ -C₄)-halogen alkoxy and nitro, or signify inpairs a (C₂ -C₆)-alkane diyl chain and m=0 to 6, and [containing] asubstituted alkoxy group of the formula R"O--CHR'"(OR")--(C₁ -C₆)-alkoxyin which the R" signify independently of each other (C₁ -C₄)-alkyl ortogether (C₁ -C₆)-alkane diyl and R"" signifies hydrogen or (C₁-C₄)-alkyl,

by reaction with alcohols of general formula VI

    H--O--R.sup.9                                              (VI)

in which R⁹ has the significance indicated for formula V in an organicsolvent in the presence of a base.

In addition thereto, the invention also comprises the use of theoxazolidinones of general formula produced or defined herein for theα-selective production of amides of general formula VII ##STR7## inwhich R¹ and R⁵ have the significance indicated for formula I and R¹⁰and R¹¹ have the significance, independently of one another and equallyor differently, of R⁹ and can, moreover, be combined with one another toa ring

by reaction with amines with amines of general formula VIII ##STR8## inwhich R¹⁰ and R¹¹ have the significance indicated for formula VII in anorganic solvent in the presence of a base.

The use of the oxazolidinones of the invention for producing amides byreaction with amines of general formula VIII with formula VIII standingfor L-phenylalaninemethyl ester,D-alanine-2,2,4,4-tetramethylthietan-3-yl amide or D-arnino butyricacid-(2S)-phenyl-propanamide or in which R¹⁰ =R¹¹ =n-pentyl or R¹⁰=n-pentyl and R¹¹ =3-methoxy-n-propyl is especially preferred.

Thus, the invention also finally comprises a method for the α-selectiveproduction of esters and amides of general formula V or VII which ischaracterized in that N-acyl-oxazolidinones of general formula I arebrought to reaction with alcohols or amines of general formula VI orVIII in an organic solvent in the presence of an auxiliary base and thatin order to produce the oxazolidinone of general formula I aldehydes orketones of general formula III are reacted with N-acyl-amino acidanhydrides of general formula II at rather high temperatures, preferably50° C., especially preferably temperatures above 50° C. and quiteespecially preferably temperatures above 100° C., preferably in thepresence of a catalytic amount of acids. In addition, the amino acids ofgeneral formula IV can be brought to a reaction with aldehydes orketones of general formula III.

In a preferred method variant of the invention an inert organic solventis used in which oxazolidinones of general formula I and alcohols oramines of general formulas VI and VIII dissolve to an extent sufficientfor the course of the reaction, preferably ether, halogenated solventsor sterically exacting alcohols, with iospropanol or 2-butanol beingespecially preferred.

In an advantageous method variant all basic compounds can be used asbase which dissolve in the organic solvent in which the reaction takesplace and which do not react themselves with the oxazolidinone ofgeneral formula I as well as which have a base strength sufficient fordeprotonizing the oxazolidinone of general formula I on the carboxylfunction. Tert. amines are preferred and triethylarnine or tributylamineare especially preferred.

Finally, all organic solvents in which the anhydrides of formula IIdissolve can be considered favorably as organic solvents of the reactionfor producing oxazolidinone. Short-chain carboxylic acids are preferredand acetic acid is quite especially preferred.

An economical and universally applicable method was found therewith in atotally surprising and unexpected manner for coupling, among others,aspartic acid and glutamic acid α-selectively via the anhydride routewith nucleophiles. In an advantageous modification of this method theamino dicarboxylic acid anhydrides are reacted in an organic solventwith the assistance of catalytic amounts of a strong acid with aldehydesor ketones. The oxazolidinone obtained in this manner can be couplede.g. in the presence of a base with L-Phe-OMe. Formyl-aspartame isα-selectively obtained. According to the state of the artformyl-Asp-anhydride has been used up to the present in the aspartameprocess as a reactive intermediate stage which only permits aregioisomeric ratio of α-formyl-aspartame/β-formyl-aspartame like 80/20.

The method of the invention is used with particular advantage forproducing oxazolidinones of aspartic acid. These compounds have asignificant position as intermediate stage for dipeptide sweeteners.

Furthermore, it is preferred according to the invention to heat a formylamino acid anhydride of general formula II in glacial acetic acid withparaformaldehyde in the presence of catalytic amounts of paratoluenesulfonic acid to 100° C. This strategy allows the complete reaction ofthe anhydride to the oxazolidinone of general formula I (R², R³ =H). Thefollowing example explains the invention:

EXAMPLE 1

Production of 4-carboxymethyl-3-formyl-1,3-oxazolidin-5-one

14.3 g (100 mmol) of formyl aspartic acid anhydride are charged into a100° C. solution of 9 g (300 mmol) paraformaldehyde in 200 ml glacialacetic acid. After 30 min the mixture is cooled to 50° C. and the aceticacid removed in a vacuum. Then, the yellowish oily residue is taken upin a little saturated sodium hydrogen carbonate solution and extractedseveral times after acidification of the aqueous solution to pH 1.5 withethyl acetate. The collected organic phases are dried over magnesiumsulfate and then filtered. After removal of the solvent in a vacuum ayellowish oil is obtained.

Production of α-Formyl Aspartic Acid Benzyl Amide

The yellowish oil of example 1, dissolved in 100 mnl isopropanol, iscompounded with 14 ml (100 mmol) triethylamine and compounded with 10 ml(100 mmol) benzylamine. The mixture is heated for 3 h to 50° C. Afterremoval of the isopropanol in a vacuum the residue is taken up in 100 ml1 N HCl, agitated 1 h and then extracted several times with ethylacetate. The saturated organic phases are dried over magnesium sulfateand after filtration the solvent is removed in a vacuum. 20 g (80 mmol)80% of a slightly yellowish solid is obtained.

EXAMPLE 2

Production of α-Formyl Aspartic Acid Methyl Ester

1 equiv. Of a solution of NaOMe in MeOH is added dropwise to a solutionof For-oxazolidinone (˜100 mmol) in methanol (50 ml) at -10° C. Thesolution is then put on 1 N HCl (100 ml) and extracted twice with ethylacetate (100 ml). Thee organic phases are dried over magnesium sulfateand the residue obtained after removal of the solvent in a vacuum ispurified on silica gel. The α-methyl ester of For-aspartic acid isobtained in 80% yield.

What is claimed is:
 1. Oxazolidinones of formula I ##STR9## in which R¹signifies hydrogen;R² and R³ signify, independently of one another andequally or differently hydrogen, (C₁ -C₈)-alkyl or (C₃ -C₈)-alkenyl, (C₃-C8)-alkinyl or (C₃ -C₈) -cycloalkyl, which above groups having carboncan be unsubstituted or substituted singly or multiply, up to threetimes, by equal or different groups from the group having, hydroxy, (C₁-C₈)-alkoxy, (C₁ -C₈)-alkylmercapto, C₂ -C₈)-alkenylmercapto, (C₂-C₈)-alkinylmercapto, (C₂ -C₈)-alkenyloxy, (C₂ -C₈)-alkinyloxy, (C₃-C₇)-cycloalkyl, (C₃ -C₇)-cycloalkoxy, cyano, mono- and di-(C₁-C4-alkyl)-amino, phenyl, phenyl -(C₁ -C₆)-alkoxy, which last two groupscited in the phenyl ring can be unsubstituted or substituted singly ormultiply up to three times, by equal or different groups from the groupof halogen, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, (C₁ -C₄)-halogen alkyl, (C₁-C₄)-halogen alkoxy wherein both R² and R³ are not concomitantlyt-butyl; and R⁴ signifies hydrogen, (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl,(C₂ -C₆)-alkinyl, aryl, alkaryl, arylalkyl or cycloalkyl, wherein linearor branched alkyl groups optionally may have at least one heteroatomsubstitution selected from the group consisting of N, O and S, with theproviso that the cycloalkyl or aryl groups are not heterocycles; R⁵signifies a (C₁ -C₂)-alkane diyl chain which can be substituted with upto two (C₁ -C₄)-alkyl groups, (C₃ -C₄)-alkenyl groups, (C₃ -C₄)-alkinylgroups, (C₃ -C₈)-cycloalkyl groups and/or aryl groups, wherein saidalkane diyl chain or its substituents may optionally have at least oneheteroatom substitution selected from the group consisting of N, O andS, with the proviso that the cycloalkyl or aryl groups are notheterocycles; and two of the substituents of the alkane diyl chain canbe connected to one another or to one of the substituents of the alkanediyl chain with an R⁴ group, to form a ring structure, with the provisothat the formed ring structure is not a heterocycle; with the exceptionof the oxazolidinone of formula I wherein R² ═H, R³ ═CCl₃, R⁵ ═CH₂ andR⁴ ═H.
 2. Oxazolidinones according to claim 1, characterized in that R⁴═H and R⁵ is --CH₂ -- or --CH₂ --CH₂ --.
 3. Oxazolidinones according toclaim 1 or 2, characterized in that R² and R³ are each hydrogen.